Iron deficiency anemia and malaria are interconnected global health concerns. Iron deficiency anemia (IDA) causes significant health deficits in pregnant women and children in the developing world and requires iron supplementation. Paradoxically, evidence suggests IDA protects against Plasmodium falciparum malaria infection. Thus the need for iron supplementation creates a public health dilemma in malaria endemic areas. Physiologically, IDA alters erythropoiesis and red blood cells (RBCs) as well as innate immune function, which may considerably impact the symptomatic RBC stage of P. falciparum infection. Though epidemiological data suggest iron supplementation increases malaria susceptibility, the magnitude and biology of risk remain uncertain. Previously it was believed iron deficiency inhibited malaria growth through iron deprivation, as is the case with other pathogens. However, our work has generated a novel explanation for the effect of iron deficiency on parasite growth. Our preliminary data showing P. falciparum less frequently invades and replicates less efficiently in IDA RBC suggest changes in RBC properties and the RBC population structure drive IDA resistance to malaria. Still, the precise molecular mechanisms of IDA resistance remain unknown. The long term goal is to further understand natural alterations in human RBC physiology that confer resistance to malaria infection, in order to direct IDA management in malaria endemic areas. Our overarching hypothesis is that natural alterations in human RBC physiology caused by host iron deficiency reduce the ability of malaria parasites to both invade and grow in IDA RBCs. Specifically, we will define the physiological properties of IDA RBC membranes that reduce invasion by the merozoite stage of the parasite (AIM 1). In addition, we will assess whether the parasite uses different RBC invasion pathways to infect IDA RBCs and determine the precise step(s) in merozoite RBC invasion impacted by host iron deficiency (AIM 2). The proposal aims will determine the critical molecular properties of IDA RBCs that serve to protect against malaria infection. This is essential in planning how to avoid risks accompanying iron supplementation in malaria endemic areas. Furthermore, like the hemoglobinopathies, natural resistance of IDA can be exploited to better understand parasite pathogenesis and identify blood stage vaccine and drug targets. Finally, with this carefully constructed research and training plan, the trainee will develop advanced skills in molecular biology and parasitology, including research design, data collection, and analysis; as well as acquire clinical and translational research skills to facilitae integration of clinical and research interests in infectious diseases.